Genetically increasing flux through b-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance

Cody D. Smith, Chien Te Lin, Shawna L McMillin, Luke A. Weyrauch, Cameron A. Schmidt, Cheryl A. Smith, Irwin J. Kurland, Carol A. Witczak, P. Darrell Neufer

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Elevated mitochondrial hydrogen peroxide (H2O2) emission and an oxidative shift in cytosolic redox environment have been linked to high-fat-diet-induced insulin resistance in skeletal muscle. To test specifically whether increased flux through mitochondrial fatty acid oxidation, in the absence of elevated energy demand, directly alters mitochondrial function and redox state in muscle, two genetic models characterized by increased muscle b-oxidation flux were studied. In mice overexpressing peroxisome proliferator-activated receptor-a in muscle (MCK-PPARa), lipid-supported mitochondrial respiration, membrane potential (DWm), and H2O2 production rate (JH2O2) were increased, which coincided with a more oxidized cytosolic redox environment, reduced muscle glucose uptake, and whole body glucose intolerance despite an increased rate of energy expenditure. Similar results were observed in lipin-1-deficient, fatty-liver dystrophic mice, another model characterized by increased b-oxidation flux and glucose intolerance. Crossing MCAT (mitochondria-targeted catalase) with MCK-PPARa mice normalized JH2O2 production, redox environment, and glucose tolerance, but surprisingly, both basal and absolute insulin-stimulated rates of glucose uptake in muscle remained depressed. Also surprising, when placed on a high-fat diet, MCK-PPARa mice were characterized by much lower whole body, fat, and lean mass as well as improved glucose tolerance relative to wild-type mice, providing additional evidence that overexpression of PPARa in muscle imposes more extensive metabolic stress than experienced by wild-type mice on a high-fat diet. Overall, the findings suggest that driving an increase in skeletal muscle fatty acid oxidation in the absence of metabolic demand imposes mitochondrial reductive stress and elicits multiple counterbalance metabolic responses in an attempt to restore bioenergetic homeostasis. NEW & NOTEWORTHY Prior work has suggested that mitochondrial dysfunction is an underlying cause of insulin resistance in muscle because it limits fatty acid oxidation and therefore leads to the accumulation of cytotoxic lipid intermediates. The implication has been that therapeutic strategies to accelerate b-oxidation will be protective. The current study provides evidence that genetically increasing flux through b-oxidation in muscle imposes reductive stress that is not beneficial but rather detrimental to metabolic regulation.

Original languageEnglish (US)
Pages (from-to)E938-E950
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number5
StatePublished - May 2021

Bibliographical note

Funding Information:
This work was supported by funding from Einstein-Mt. Sinai National Institutes of Health (NIH) P60 DK020541 (to I. J. K.), NIH F31 DK119080 (to S. L. M.), and NIH R01s DK103562 (to C. A. W.) and DK096907 and DK110656 (to P. D. N).

Publisher Copyright:
Copyright © 2021 the American Physiological Society.


  • Fat oxidation
  • Glucose tolerance
  • Insulin resistance
  • Mitochondria
  • Skeletal muscle


Dive into the research topics of 'Genetically increasing flux through b-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance'. Together they form a unique fingerprint.

Cite this